Indole N ‐Linked Hydroperoxyl Adduct of Protein‐Derived Cofactor Modulating Catalase‐Peroxidase Functions
Year: 2024
Type: article
Abstract: Bifunctional catalase-peroxidase (KatG) features a posttranslational methionine-tyrosine-tryptophan (MYW) crosslinked cofactor crucial for its catalase function, enabling pathogens to neutralize hydrogen peroxide during infection. We discovered the presence of indole nitrogen-linked hydroperoxyl adduct (MYW-OOH) in Mycobacterium tuberculosis KatG in the solution state under ambient conditions, suggesting its natural occurrence. By isolating predominantly MYW-OOH-containing KatG protein, we investigated the chemical stability and functional impact of MYW-OOH. We discovered that MYW-OOH inhibits catalase activity, presenting a unique temporary lock. Exposure to peroxide or increased temperature removes the hydroperoxyl adduct from the protein cofactor, converting MYW-OOH to MYW and restoring the detoxifying ability of the enzyme against hydrogen peroxide. Thus, the N-linked hydroperoxyl group is releasable. KatG with MYW-OOH represents a catalase dormant, but primed, state of the enzyme. These findings provide insight into chemical strategies targeting the bifunctional enzyme KatG in pathogens, highlighting the role of N-linked hydroperoxyl modifications in enzymatic function.
Language: English
Subfield: Inorganic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
Funders: National Science Foundation, U.S. Department of Energy, Welch Foundation, University of Texas at San Antonio, National Institutes of Health, Directorate for Biological Sciences, Directorate for Mathematical and Physical Sciences, Office of Science, National Institute of General Medical Sciences, Division of Chemistry, Basic Energy Sciences, Biological and Environmental Research, Argonne National Laboratory
Awards: G102163711, G107546177, G1134986084, G1229526393, G1286251239, G1313983767, G1664757510, G1725900305, G2168029778, G2287611682, G2371548206, G262962599, G2857925935, G2961846298, G303061748, G3075337988, G3093431617, G315621713, G409777406, G426311843, Cys-Tyr Cofactor in Iron and Copper Proteins, G4581610328, G4741855258, G495301720, G498139845, G513797252, G5387317844, G5570207115, G5607048534, G5775502806, G618388848, G6550344761, G6848031779, G6918803902, G7283024673, G7583137537, G7932029974, Conduits and Control of KatG Intramolecular Electron Transfer: Formation and Operation of a Novel Cofactor, G8368897450, G8382000481, G8925327636, G9000332219, A Synchrotron Radiation Structural Biology Resource, G911061179, G969889393, G993149817
OpenAlex ID: W4402692463